1 INTRODUCTION
Baloxavir marboxil—an inhibitor of influenza cap-dependent endonuclease—is a new class of antiviral drug against seasonal influenza [1,2]. In 2018, baloxavir was approved in Japan and the US [3]; the drug was first approved for the indication for otherwise healthy persons with uncomplicated influenza, but the indication has now expanded to persons at high-risk of influenza complications [4]. Baloxavir was estimated to have been prescribed for more than five million persons during the 2018/2019 influenza season in Japan, representing 40% of all antivirals prescribed in the country for influenza [5].
In prelicensure phase 2/3 trials, the clinical efficacy of baloxavir was superior to that of a placebo and similar to that of oseltamivir, with respect to symptom duration [6]. However, viral mutations conferring less susceptibility to baloxavir—amino acid substitutions at position 38 of polymerase acidic protein—were reported in 2.2% of 182 and 9.7% of 370 baloxavir recipients in the phase 2 and 3 trials, respectively. This group of patients experienced a longer median time to alleviation of symptoms than baloxavir recipients without shedding variant strain [7]. According to surveillance data from the 2018/2019 season in Japan, 1.7% (6/343) of A (H1N1) strain and 9.5% (34/357) of A (H3N2) strain exhibited reduced susceptibility to baloxavir from specimens obtained from both treated and untreated persons [8]. This raises a concern for high proportion of variant virus and changes in the clinical course of affected cases [9]. However, the clinical consequence of variant virus is not fully understood in clinical and public health perspective, due to the sparse data of this novel drug from non-trial setting.
In this study, we hypothesized that baloxavir recipients shedding variant virus less susceptible to this drug utilized more medical resources if their symptoms were subsequently prolonged. Using a large-scale observational data in Japan, we sought to assess the association between baloxavir use and subsequent medical resource use among children, a group in which the risk of the virus developing reduced susceptibility to baloxavir is high [10].